Fused heterocyclic ring compounds and method of treating retinal disease using same

Abstract

The present invention relates to a novel indene derivative, a preparation method for the same, and a pharmaceutical composition for treating retinal disease comprising the same as an active ingredient. The novel indene derivative of the present invention, the optional isomer of the same, or the pharmaceutically acceptable salts of the same have excellent inhibitory efficiency of receptor-interacting serine-threonine-protein kinase 1 (RIPK1). Therefore, the composition containing the same as an active ingredient can be effectively used as a pharmaceutical composition for treating retinal disease.

What is claimed is: 
     
       1. A compound, an optical isomer, or a pharmaceutically acceptable salt of the same, wherein the compound is selected from the group consisting of:
 (1) (4-bromo-7-chlorothieno[2,3-c]pyridine-2-yl)(morpholino)methanone; 
 (2) (4-(4-fluorophenyl)thieno[2,3-c]pyridine-2-yl)(morpholino)methanone; 
 (3) (4-bromothieno[2,3-c]pyridine-2-yl)(morpholino)methanone; 
 (4) (4-(4-fluorophenyl)thieno[2,3-b]pyridine-2-yl)(morpholino)methanone; 
 (5) (7-chloro-4-(4-fluorophenyl)thieno[2,3-c]pyridine-2-yl)(morpholino)methanone; 
 (7) 4-((4-(4-fluorophenyl)benzo[b]thiophene-2-yl)methyl)morpholine; 
 (8) 4-(4-(4-fluorophenyl)benzo[b]thiophene-2-carbonyl)morpholine-3-carboxylic acid; 
 (9) (4-(1H-indole-5-yl)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (10) N-(4-(2-(morpholine-4-carbonyl)benzo[b]thiophene-4-yl)phenyl)acetamide; 
 (14) (5-bromo-1H-benzo[d]imidazole-2-yl)(morpholino)methanone; 
 (17) (4,6-dimethylbenzo[b]thiophene-2-yl)(morpholino)methanone; 
 (18) (6,7-dimethylbenzo[b]thiophene-2-yl)(morpholino)methanone; 
 (19) (6-methoxybenzo[b]thiophene-2-yl)(morpholino)methanone; 
 (20) N,N-diethyl-2-(morpholine-4-carbonyl)benzo[b]thiophene-4-carboxamide; 
 (24) (5-methoxy-1H-benzo[d]imidazole-2-yl)(morpholino)methanone; 
 (27) (6-methylbenzofuran-2-yl)(morpholino)methanone; 
 (29) (7-bromobenzo[b]thiophene-2-yl)(morpholino)methanone; 
 (30) (4-(2-fluorophenyl)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (31) (4-(biphenyl-4-yl)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (32) morpholino(4-p-tolylbenzo[b]thiophene-2-yl)methanone; 
 (33) 4-(2-(morpholine-4-carbonyl)benzo[b]thiophene-4-yl)benzoic acid; 
 (34) (4-(4-methoxyphenyl)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (35) (4-(4-fluorophenyl)benzo[b]thiophene-2-yl)(pyrrolidine-1-yl)methanone; 
 (36) (4-(3-fluorophenyl)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (37) (4-aminopiperidine-1-yl)(4-(4-fluorophenyl)benzo[b]thiophene-2-yl)methanone hydrochloride; 
 (38) (4-(4-fluorophenyl)benzo[b]thiophene-2-yl)(piperazine-1-yl)methanone hydrochloride; 
 (39) (4-(4-fluorophenyl)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (40) (5-(4-fluorophenyl)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (41) (4-(biphenyl-3-yl)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (42) (4-(3-aminophenyl)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (43) 4-(2-(morpholine-4-carbonyl)benzo[b]thiophene-4-yl)benzamide; 
 (44) (4-(4-hydroxyphenyl)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (45) morpholino(4-(4-(trifluoromethoxy)phenyl)benzo[b]thiophene-2-yl)methanone; 
 (46) (4-(4-fluorophenyl)benzo[b]thiophene-2-yl)(oxazolidine-3-yl)ethanone; 
 (47) (4-(4-fluorophenyl)benzo[b]thiophene-2-yl)(piperidine-1-yl)methanone; 
 (48) (4-(4-fluorophenyl)benzo[b]thiophene-2-yl)(4-hydroxypiperidine-1-yl)methanone; 
 (49) (4-(4-fluorophenyl)benzo[b]thiophene-2-yl)(4-methylpiperazine-1-yl)methanone hydrochloride; 
 (50) (4-(4-(methylthio)phenyl)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (51) (4-(4-fluorophenyl)benzo[b]thiophene-2-yl)(thiomorpholino)methanone; 
 (52) (4-(4-fluorophenyl)benzo[b]thiophene-2-yl)(1,4-oxazepane-4-yl)ethanone; 
 (53) (7-chloro-4-(4-fluorophenyl)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (54) (4-(4-bromophenyl)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (55) (4-(6-methoxypyridine-3-yl)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (56) (4-(3-fluorobenzyl)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (57) (4-(2,4-difluorobenzyl)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (58) (4-(2,4-difluorophenylamino)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (59) (4-(4-fluorophenoxy)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (60) (4-(4-fluorophenethyl)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (61) (4-(4-fluorobenzyloxy)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (62) (4-(4-fluorobenzylsulfonyl)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (63) (4-(2,4-difluorophenyl)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (64) methyl 4-(2-(morpholine-4-carbonyl)benzo[b]thiophene-4-yl)benzene sulfiante; 
 (65) (7-(4-fluorophenyl)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (66) (4-(6-fluoropyridine-3-yl)benzo[b]thiophene-2-yl)(morpholino)methanone hydrochloride; 
 (67) (4-(4-fluorobenzyl)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (68) (4-(4-fluorophenylamino)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (69) (4-((4-fluorophenyl)(methyl)amino)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (70) 4-fluoro-N-(2-(morpholine-4-carbonyl)benzo[b]thiophene-4-yl)benzenesulfonamide; 
 (71) (4-(4-fluorobenzylthio)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (72) 1-methyl-5-(2-(morpholine-4-carbonyl)benzo[b]thiophene-4-yl)-1H-pyrrole-2-carbonitrile; 
 (73) (4-(1-methyl-1H-pyrazol-4-yl)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (74) morpholino(4-(thiophene-2-yl)benzo[b]thiophene-2-yl)methanone; 
 (75) (4-(furan-3-yl)benzo[b]thiophene-2-yl)(morpholino)methanone; and 
 (76) morpholino(4-(thiophene-3-yl)benzo[b]thiophene-2-yl)methanone. 
 
     
     
       2. A pharmaceutical composition for the treatment of retinal disease comprising the compound of  claim 1 , the optical isomer thereof, or the pharmaceutically acceptable salt of the same as an active ingredient, and a pharmaceutical acceptable carrier. 
     
     
       3. The pharmaceutical composition for the treatment of retinal disease according to  claim 2 , wherein the compound is characterized by inhibiting receptor-interacting serine/threonine-protein kinase 1. 
     
     
       4. The pharmaceutical composition for the treatment of retinal disease according to  claim 2 , wherein the retinal disease is selected from the group consisting of retinitis pigmentosa (RP), Leber congenital amaurosis (LCA), Stargardts disease, Usher syndrome, choroideremia, rod-cone or cone-rod dystrophy, ciliopathy, mitochondrial disorders, progressive retinal atrophy, degenerative retinal diseases, age-related macular degeneration (AMD), wet AMD, dry AMD, geographical atrophy, inherited or acquired macular degeneration, retinal photoreceptor diseases, retinal pigment epithelial diseases, diabetic retinopathy, cystic macular edema, uveitis, retinal detachment, traumatic retinal injury, iatrogenic retinal injury, macular holes, macular capillarectasia, ganglion cell diseases, optic nerve diseases, glaucoma, optic neuropathy, ischemic retinal diseases, retinopathy of prematurity, occlusion of retinal vessels, inherited macroaneurysm, retinal vascular diseases, ophthalmic vascular diseases, glaucomatous retinal neurodegeneration, and ischemic optic neuropathy. 
     
     
       5. A method of treating retinal disease in a subject, comprising administering to the subject an effective amount of a compound, an optical isomer, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
 (1) (4-bromo-7-chlorothieno[2,3-c]pyridine-2-yl)(morpholino)methanone; 
 (2) (4-(4-fluorophenyl)thieno[2,3-c]pyridine-2-yl)(morpholino)methanone; 
 (3) (4-bromothieno[2,3-c]pyridine-2-yl)(morpholino)methanone; 
 (4) (4-(4-fluorophenyl)thieno[2,3-b]pyridine-2-yl)(morpholino)methanone; 
 (5) (7-chloro-4-(4-fluorophenyl)thieno[2,3-c]pyridine-2-yl)(morpholino)methanone; 
 (6) morpholino(naphtho[1,2-b]thiophene-2-yl)methanone; 
 (7) 4-((4-(4-fluorophenyl)benzo[b]thiophene-2-yl)methyl)morpholine; 
 (8) 4-(4-(4-fluorophenyl)benzo[b]thiophene-2-carbonyl)morpholine-3-carboxylic acid; 
 (9) (4-(1H-indole-5-yl)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (10) N-(4-(2-(morpholine-4-carbonyl)benzo[b]thiophene-4-yl)phenyl)acetamide; 
 (11) (5-hydroxy-1H-indole-2-yl)(morpholino)methanone; 
 (12) (5-chloro-1H-indole-2-yl)(morpholino)methanone; 
 (13) (5-methyl-1H-benzo[d]imidazole-2-yl)(morpholino)methanone; 
 (14) (5-bromo-1H-benzo[d]imidazole-2-yl)(morpholino)methanone; 
 (15) benzofuran-2-yl(morpholino)methanone; 
 (16) (5-bromobenzofuran-2-yl)(morpholino)methanone; 
 (17) (4,6-dimethylbenzo[b]thiophene-2-yl)(morpholino)methanone; 
 (18) (6,7-dimethylbenzo[b]thiophene-2-yl)(morpholino)methanone; 
 (19) (6-methoxybenzo[b]thiophene-2-yl)(morpholino)methanone; 
 (20) N,N-diethyl-2-(morpholine-4-carbonyl)benzo[b]thiophene-4-carboxamide; 
 (21) (5-methyl-1H-indole-2-yl)(morpholino)methanone; 
 (22) (5-methoxy-1H-indole-2-yl)(morpholino)methanone; 
 (23) (1H-benzo[d]imidazole-2-yl)(morpholino)methanone; 
 (24) (5-methoxy-1H-benzo[d]imidazole-2-yl)(morpholino)methanone; 
 (25) (1-methyl-1H-indole-2-yl)(morpholino)methanone; 
 (26) (5-methoxybenzofuran-2-yl)(morpholino)methanone; 
 (27) (6-methylbenzofuran-2-yl)(morpholino)methanone; 
 (28) (5-aminobenzo[b]thiophene-2-yl)(morpholino)methanone; 
 (29) (7-bromobenzo[b]thiophene-2-yl)(morpholino)methanone; 
 (30) (4-(2-fluorophenyl)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (31) (4-(biphenyl-4-yl)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (32) morpholino(4-p-tolylbenzo[b]thiophene-2-yl)methanone; 
 (33) 4-(2-(morpholine-4-carbonyl)benzo[b]thiophene-4-yl)benzoic acid; 
 (34) (4-(4-methoxyphenyl)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (35) (4-(4-fluorophenyl)benzo[b]thiophene-2-yl)(pyrrolidine-1-yl)methanone; 
 (36) (4-(3-fluorophenyl)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (37) (4-am inopiperidine-1-yl)(4-(4-fluorophenyl)benzo[b]thiophene-2-yl)methanone hydrochloride; 
 (38) (4-(4-fluorophenyl)benzo[b]thiophene-2-yl)(piperazine-1-yl)methanone hydrochloride; 
 (39) (4-(4-fluorophenyl)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (40) (5-(4-fluorophenyl)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (41) (4-(biphenyl-3-yl)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (42) (4-(3-aminophenyl)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (43) 4-(2-(morpholine-4-carbonyl)benzo[b]thiophene-4-yl)benzamide; 
 (44) (4-(4-hydroxyphenyl)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (45) morpholino(4-(4-(trifluoromethoxy)phenyl)benzo[b]thiophene-2-yl)methanone; 
 (46) (4-(4-fluorophenyl)benzo[b]thiophene-2-yl)(oxazolidine-3-yl)methanone; 
 (47) (4-(4-fluorophenyl)benzo[b]thiophene-2-yl)(piperidine-1-yl)methanone; 
 (48) (4-(4-fluorophenyl)benzo[b]thiophene-2-yl)(4-hydroxypiperidine-1-yl)methanone; 
 (49) (4-(4-fluorophenyl)benzo[b]thiophene-2-yl)(4-methylpiperazine-1-yl)methanone hydrochloride; 
 (50) (4-(4-(methylthio)phenyl)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (51) (4-(4-fluorophenyl)benzo[b]thiophene-2-yl)(thiomorpholino)methanone; 
 (52) (4-(4-fluorophenyl)benzo[b]thiophene-2-yl)(1,4-oxazepane-4-yl)methanone; 
 (53) (7-chloro-4-(4-fluorophenyl)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (54) (4-(4-bromophenyl)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (55) (4-(6-methoxypyridine-3-yl)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (56) (4-(3-fluorobenzyl)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (57) (4-(2,4-difluorobenzyl)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (58) (4-(2,4-difluorophenylamino)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (59) (4-(4-fluorophenoxy)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (60) (4-(4-fluorophenethyl)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (61) (4-(4-fluorobenzyloxy)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (62) (4-(4-fluorobenzylsulfonyl)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (63) (4-(2,4-difluorophenyl)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (64) methyl 4-(2-(morpholine-4-carbonyl)benzo[b]thiophene-4-yl)benzene sulfiante; 
 (65) (7-(4-fluorophenyl)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (66) (4-(6-fluoropyridine-3-yl)benzo[b]thiophene-2-yl)(morpholino)methanone hydrochloride; 
 (67) (4-(4-fluorobenzyl)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (68) (4-(4-fluorophenylamino)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (69) (4-((4-fluorophenyl)(methyl)amino)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (70) 4-fluoro-N-(2-(morpholine-4-carbonyl)benzo[b]thiophene-4-yl)benzenesulfonamide; 
 (71) (4-(4-fluorobenzylthio)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (72) 1-methyl-5-(2-(morpholine-4-carbonyl)benzo[b]thiophene-4-yl)-1H-pyrrole-2-carbonitrile; 
 (73) (4-(1-methyl-1H-pyrazol-4-yl)benzo[b]thiophene-2-yl)(morpholino)methanone; 
 (74) morpholino(4-(thiophene-2-yl)benzo[b]thiophene-2-yl)methanone; 
 (75) (4-(furan-3-yl)benzo[b]thiophene-2-yl)(morpholino)methanone; and 
 (76) morpholino(4-(thiophene-3-yl)benzo[b]thiophene-2-yl)methanone. 
 
     
     
       6. The method of treating retinal disease according to  claim 5 , wherein the compound is characterized by inhibiting receptor-interacting serine/threonine-protein kinase 1. 
     
     
       7. The method of treating retinal disease according to  claim 5 , wherein the retinal disease is selected from the group consisting of retinitis pigmentosa (RP), Leber congenital amaurosis (LCA), Stargardts disease, Usher syndrome, choroideremia, rod-cone or cone-rod dystrophy, ciliopathy, mitochondrial disorders, progressive retinal atrophy, degenerative retinal diseases, age-related macular degeneration (AMD), wet AMD, dry AMD, geographical atrophy, inherited or acquired macular degeneration, retinal photoreceptor diseases, retinal pigment epithelial diseases, diabetic retinopathy, cystic macular edema, uveitis, retinal detachment, traumatic retinal injury, iatrogenic retinal injury, macular holes, macular capillarectasia, ganglion cell diseases, optic nerve diseases, glaucoma, optic neuropathy, ischemic retinal diseases, retinopathy of prematurity, occlusion of retinal vessels, inherited macroaneurysm, retinal vascular diseases, ophthalmic vascular diseases, glaucomatous retinal neurodegeneration, and ischemic optic neuropathy.